On December 7, 2019 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported results of a 7.5-year pooled analysis showing earlier treatment with IMBRUVICA (ibrutinib) monotherapy compared to later lines of therapy (LOT) extended progression-free survival (PFS) and increased the likelihood of a complete response (CR) in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) – demonstrating that some patients achieved a disappearance of any signs of disease (Press release, AbbVie, DEC 7, 2019, View Source [SID1234552032]).

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The updated pooled analysis includes three clinical trials: Phase 2 SPARK, Phase 3 RAY and Phase 2 PCYC-1104. Patients achieving a CR with IMBRUVICA had a strong response, with a median duration of therapy longer than 5.5 years. These results were presented today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

"MCL is an aggressive B-cell malignancy in which most patients have poor prognosis and are likely to relapse after their initial line of therapy. For those treated with chemotherapy, progression-free survival generally declines with each successive line of treatment," said Simon Rule, M.D., Professor in Haematology, Peninsula Medical School, University of Plymouth, United Kingdom. "These extended follow-up results from the pooled analysis of ibrutinib compared to prior regimens are very encouraging for patients with relapsed or refractory MCL – as they showed treatment with ibrutinib at first relapse versus later lines of therapy resulted in a median progression-free survival of longer than two years."

"Building on the legacy of IMBRUVICA, these latest pooled data presented at ASH (Free ASH Whitepaper), which represent the longest follow-up to-date in mantle cell lymphoma, add to the unprecedented body of evidence supporting the use of IMBRUVICA monotherapy to treat this rare and aggressive form of non-Hodgkin’s lymphoma," said Danelle James, M.D., M.A.S., IMBRUVICA Clinical Development Lead, Pharmacyclics LLC, an AbbVie company. "We continue to be pleased by the proven efficacy and safety profile of this pioneering BTK inhibitor, which has shown to delay disease progression and improve durable responses when used at first relapse."

IMBRUVICA is a once-daily, first-in-class Bruton’s tyrosine kinase (BTK) inhibitor that is administered orally, and is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Abstract #1538: Long-term outcomes with IMBRUVICA versus the prior regimen: a pooled analysis in relapsed/refractory MCL with up to 7.5 years of extended follow-up

Poster Presentation: Saturday, December 7 at 5:30 p.m. EST

The pooled analysis evaluated 370 patients with R/R MCL (median 2 [range 1-9] prior LOTs) enrolled in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies who received IMBRUVICA 560 mg orally once daily. For the regimen prior to IMBRUVICA, time to next treatment (TTNT) was used as a surrogate for PFS. Progression of disease (POD) on frontline treatment was categorized as early (TTNT less than 24 months) or late (TTNT of 24 months or longer). The median follow-up and exposure for IMBRUVICA-treated patients were 41 months (0.2 – 92.4) and 11.1 months (0.03 – 92.4), respectively. Treatment duration was three years or more in 22.4 percent of patients.

Results showed overall median PFS on IMBRUVICA was 12.5 months (9.8 – 16.6) compared to median TTNT on the prior regimen of 10.9 months (9.1-12.6). PFS for patients who received IMBRUVICA was longer than TTNT on the prior regimen for 50 percent of patients; for 27 percent of patients, PFS was longer than TTNT on the prior regimen by 12 months or more. At five years, PFS rate was 19 percent and overall survival (OS) rate was 41 percent. In patients with one prior LOT, median PFS was 25.4 months (17.5 – 51.8) and OS was 61.6 months (36.0 – not estimable [NE]). In patients with a CR, median PFS was 67.7 months (51.7 – NE) and OS was not reached (NE-NE).

Additionally, of the 99 patients who received IMBRUVICA in second-line, 43 percent had early frontline POD and 57 percent of them had late frontline POD. In patients with early frontline POD, median PFS with IMBRUVICA (13.8 months) was similar to median frontline TTNT (14.0 months); median duration of response (DOR) and OS on IMBRUVICA were 22.1 and 23.5 months, respectively. In patients with late frontline POD, median PFS with IMBRUVICA (57.5 months) was longer than median frontline TTNT (42.2 months); median DOR and OS on IMBRUVICA were not reached.

With up to 92 months of follow-up, 81.6 percent of patients had Grade 3 or higher treatment-emergent adverse events (TEAEs) and 64.9 percent had serious adverse events (SAEs). The most common Grade 3 or higher TEAEs were neutropenia (17 percent), pneumonia (13.5 percent) and thrombocytopenia (12.4 percent). The most common SAEs were pneumonia (13.2 percent), atrial fibrillation (5.7 percent), and dyspnea (4.3 percent).

About IMBRUVICA

IMBRUVICA (ibrutinib) is an oral, once-daily medicine that works differently than chemotherapy as it blocks a protein called Bruton’s tyrosine kinase (BTK). The BTK protein sends important signals that tell B cells to mature and produce antibodies. BTK signaling is needed by specific cancer cells to multiply and spread. By blocking BTK, IMBRUVICA may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.

Since its launch in 2013, IMBRUVICA has received 10 FDA approvals across six disease areas:
chronic lymphocytic leukemia (CLL) with or without 17p deletion (del17p); small lymphocytic lymphoma (SLL) with or without del17p; Waldenström’s macroglobulinemia (WM); previously-treated patients with mantle cell lymphoma (MCL)*; previously-treated patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy* – and previously-treated patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

IMBRUVICA is now approved in 95 countries and has been used to treat more than 170,000 patients worldwide across its approved indications. IMBRUVICA is the only FDA-approved medicine in WM and cGVHD. IMBRUVICA has been granted four Breakthrough Therapy Designations from the U.S. FDA. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA was one of the first medicines to receive FDA approval via the Breakthrough Therapy Designation pathway.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL recommends ibrutinib (IMBRUVICA) as a preferred regimen for the initial treatment of CLL/SLL and it is the only Category 1 single-agent regimen for treatment-naïve patients without deletion 17p.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA is the most comprehensively studied BTK inhibitor, with more than 150 ongoing clinical trials. There are approximately 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and more than 100 investigator-sponsored trials and external collaborations that are active around the world. For more information, visit www.IMBRUVICA.com.

*Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 4% of patients, with fatalities occurring in 0.4% of 2,838 patients exposed to IMBRUVICA in 27 clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 39% of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood.

Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA increases the risk of major hemorrhage. In IMBRUVICA clinical trials, 3.1% of patients taking IMBRUVICA without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA. Monitor for signs and symptoms of bleeding.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.

Monitor and evaluate patients for fever and infections and treat appropriately.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA.

Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).

Monitor blood pressure in patients treated with IMBRUVICA and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA as appropriate.

Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.

Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).

The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).

Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.

cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).

The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).

Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.

*Treatment-emergent decreases (all grades) were based on laboratory measurements.

DRUG INTERACTIONS

CYP3A Inhibitors: Co-administration of IMBRUVICA with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Dose modifications of IMBRUVICA may be recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if strong inhibitors are used short-term (e.g., for ≤ 7 days). See dose modification guidelines in USPI sections 2.4 and 7.1.

CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA dose.

On December 7, 2019 Oncopeptides AB (Nasdaq Stockholm: ONCO) reported that it will present follow-up data from the pivotal Phase 2 HORIZON (OP-106) study at the ASH (Free ASH Whitepaper) Annual Meeting 2019 (Press release, Oncopeptides, DEC 7, 2019, View Source [SID1234552031]). Melflufen showed an overall response rate (ORR) of 29% and clinical benefit rate (CBR) of 37% in patients with late-stage relapsed/refractory multiple myeloma (RRMM). The safety profile remained consistent with prior reports from the HORIZON study. These data reinforce Oncopeptides’ view that melflufen can play a role in the treatment of patients with RRMM and the Company plans to submit a New Drug Application (NDA) to the FDA in the first half of 2020.

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Overall Conclusions – HORIZON Poster Presentation

Patients in the HORIZON study had a median of five prior lines of therapy, 71% of patients were triple?class refractory, 97% were refractory to the last line of treatment, and 32% suffered from extramedullary disease (EMD).
In the ITT population (n=125), the overall response rate (ORR) was 29% and the clinical benefit rate (CBR) was 37%.
In patients with triple?class refractory disease (n=97), the ORR was 24% with a median progression?free survival (PFS) of 4.0 months, a median duration of response (DOR) of 7.5 months and a median overall survival (OS) of 11.3 months.
In patients with EMD (n=42), the ORR was 24% with a median PFS of 3.0 months, a median DOR of 5.1 months and a median OS of 8.1 months.
Grade 3 and 4 Adverse Events (AE) were primarily hematologic and the incidence of non-hematologic AEs was low.
Jakob Lindberg, CEO comments:
"These data from our pivotal HORIZON study confirm that melflufen is efficacious in this late stage patient population where currently available treatment options may not be sufficient. In particular, the ORR of 24% with a DOR or 7.5 months in patients with triple-class refractory disease is impressive. The responses seen in patients with EMD are also very encouraging as no other available single agent has shown similar efficacy in this very difficult-to-treat patient population. Taken together with a relatively clean safety profile from a patient perspective, these data lead us to believe that melflufen has the potential to play an important role in the treatment of patients with relapsed/refractory multiple myeloma. Consultations with regulatory bodies are ongoing and we are planning to submit an NDA in the first half of 2020. This represents a slight change compared to previously communicated timelines after regulatory interactions have resulted in minor changes to the planned submission package."

The posters are available on the company webpage under:

www.oncopeptides.com / Investor Relations / Presentations / ASH (Free ASH Whitepaper) 2019

For more information, please contact:
Jakob Lindberg, CEO of Oncopeptides
E-mail: [email protected]
Telephone: +46 8 615 20 40

Rein Piir, Head of Investor Relations at Oncopeptides
E-mail: [email protected]
Cell phone: +46 70 853 72 92

The information in the press release is information that Oncopeptides is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact person above, on December 7, 2019 at 15.00 (CET).

About the OP-106 HORIZON study
Patient recruitment in the pivotal Phase 2 HORIZON study is completed with 157 patients enrolled. The efficacy population (n=125) reflects patients dosed on or before May 15, 2019 with additional follow?up of 20 weeks until October 1, 2019 at the time for the data cutoff. The safety population (N=154) reflects patients dosed on or before the data cutoff on October 1, 2019. The patients in the study are refractory to pomalidomide and/or daratumumab after failing on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). The HORIZON study population includes subgroups of patients who were triple?class refractory and/or had relapsing EMD and/or had cytogenetic high?risk features.

About melflufen
Melflufen is a novel peptide-drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately cleaved by peptidases to deliver an entrapped hydrophilic alkylator payload. Peptidases play a key role in protein homeostasis and feature in cellular processes such as cell-cycle progression and programmed cell death. In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular alkylator concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

On December 7, 2019 Sierra Oncology, Inc. (Nasdaq: SRRA), a late-stage drug development company focused on the development and commercialization of momelotinib, a JAK1, JAK2 & ACVR1 inhibitor with a potentially differentiated therapeutic profile for the treatment of myelofibrosis, reported new analyses of Phase 3 clinical data highlighting the anemia related benefits of momelotinib directly compared to ruxolitinib, which were presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Press release, Sierra Oncology, DEC 7, 2019, View Source [SID1234552030]).

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"Transfusion dependency and moderate to severe anemia are the most important negative prognostic factors for overall survival in myelofibrosis," said Dr. Ruben Mesa, Director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center. "These novel analyses of RBC transfusion data from the Phase 3 SIMPLIFY-1 study further demonstrate momelotinib’s compelling anemia benefits, including a substantively reduced transfusion burden compared directly with ruxolitinib, and further support momelotinib as a potentially desirable treatment option for patients with myelofibrosis."

"These retrospective analyses, performed using a variety of novel dynamic anemia benefit endpoints, underscore the demonstrably lower burden of transfusions experienced by myelofibrosis patients treated with momelotinib versus ruxolitinib in a large, blinded, randomized, clinical trial," said Dr. Nick Glover, President and CEO of Sierra Oncology. "Momelotinib uniquely inhibits ACVR1 in addition to JAK1 and JAK2, resulting in an array of distinct and clinically relevant mechanistically-based anemia benefits. While momelotinib’s favorable effect on anemia was previously demonstrated in direct comparison to ruxolitinib using a variety of standard landmark analyses of data from SIMPLIFY-1, these new analyses further describe the relative patient burden of transfusions on study, and help contrast the differences in therapeutic options for clinicians."

"Transfusion burden is a fundamental consideration in myelofibrosis, a disease characterized by chronic, progressive anemia. Specifically, preventing transfusions for patients who are currently transfusion free, or reducing or eliminating the need for transfusions for patients who are actively receiving regular blood transfusions are clinically important outcomes of direct relevance to myelofibrosis patients and their clinicians, underscoring the importance of these data," said Dr. Barbara Klencke, Chief Development Officer of Sierra Oncology. "Myelofibrosis is a disease comprising three clinical dimensions – constitutional symptoms, anemia and splenomegaly. Critically, momelotinib’s meaningful anemia benefits were achieved while also maintaining clinically comparable benefits on splenomegaly and constitutional symptoms as directly compared to ruxolitinib."

The new analyses demonstrate that:

Patients who received momelotinib had significantly decreased transfusion requirements compared to those treated with ruxolitinib, including a nearly 10-fold higher odds of receiving no transfusions during the 24-week study period (covariate ZINB model; p < 0.0001).
Patients receiving momelotinib had a significantly reduced chance of receiving one transfusion, two ‘transfusion events’ (≥ 3 RBC units) or three ‘transfusion events’ (≥ 5 RBC units).
At any given time, the mean cumulative number of RBC units received for a typical patient receiving momelotinib is approximately half of that for patients receiving ruxolitinib (HR = 0.522; p < 0.0001). Thus, for patients on momelotinib, half as many RBC units are transfused at any time as compared to ruxolitinib.
A Kaplan-Meier time-to-first RBC unit transfused analysis indicated an immediate and sustained momelotinib treatment effect compared to ruxolitinib (log-rank p < 0.0001).
A sustained and durable period of transfusion independence (TI) was maintained over long-term treatment on momelotinib. The median time to loss of TI was not reached for momelotinib-treated patients, with a follow up period exceeding 3 years.
The SIMPLIFY-1 trial was a double-blind, active-controlled Phase 3 study in which 432 patients received randomized treatment with momelotinib or ruxolitinib for 24 weeks (JCO. 2017; 35:3844–50). In addition to a significant reduction in splenomegaly and improvements in constitutional symptoms, previously reported analyses of the SIMPLIFY-1 data demonstrated that patients in the momelotinib arm achieved nominal-statistical significance for all anemia endpoints tested, including a higher rate of transfusion independence (p < 0.001) and lower rates of transfusion dependence (p = 0.019) at Week 24, compared to patients on ruxolitinib.

Sierra management will host an Analyst & Investor Event on Sunday, December 8th at 7:00 am ET to discuss these results. The event will include a presentation by renowned myelofibrosis expert, Dr. Ruben Mesa, Director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center.

Sierra recently launched the MOMENTUM Phase 3 clinical trial, a randomized double-blind trial designed to enroll 180 myelofibrosis patients who are symptomatic and anemic, and who have been treated previously with a JAK inhibitor.

About Momelotinib
Momelotinib, Sierra’s lead drug candidate, is a potent, selective and orally-bioavailable JAK1, JAK2 & ACVR1 inhibitor with a differentiated therapeutic profile in myelofibrosis encompassing robust constitutional symptom improvements, a range of meaningful anemia benefits, including eliminating or reducing the need for frequent blood transfusions, and comparable spleen control to ruxolitinib. More than 1,200 subjects have received momelotinib since clinical studies began in 2009, including more than 800 patients treated for myelofibrosis.

Chronic, progressive anemia is a key hallmark of myelofibrosis and transfusion dependence is the most important negative prognostic indicator of reduced survival in this disease. Approximately 60% of patients are anemic and 45% are transfusion dependent within one year of diagnosis, with most patients ultimately progressing to transfusion dependency. Unfortunately, currently approved JAK inhibitor therapies can induce or worsen anemia, exacerbating this significant unmet medical need in anemic myelofibrosis patients.

The marked systemic inflammation seen in myelofibrosis leads to increased ACVR1 activity which in turn increases secretion of hepcidin, resulting in perturbed iron homeostasis and an iron-restricted anemia. Momelotinib’s inhibition of ACVR1 in addition to JAK1 and JAK2, unique amongst the JAK inhibitor class, results in notable reductions of both hepcidin and inflammation, restoring iron homeostasis and RBC production, thereby alleviating anemia and transfusion dependency.

Momelotinib is an investigational drug that is not approved for any use in any country. The U.S. Food and Drug Administration has granted Fast Track designation to momelotinib for the treatment of patients with intermediate/high-risk myelofibrosis who have previously received a JAK inhibitor. Momelotinib is wholly owned by Sierra Oncology and is protected by patents anticipated to provide potential exclusivity to 2040 in the United States and Europe (including Patent Term Extension or Supplementary Protection Certificate).

Analyst and Investor Event and Webcast Information
Sierra Oncology will host an Analyst & Investor Event to discuss these data being presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida. The event will be led by Dr. Nick Glover, President and CEO of Sierra Oncology, and include a presentation by Dr. Ruben Mesa.

Date and Time: Sunday, December 8th at 7:00 – 8:00 am ET
Location: Bayhill 33 Meeting Room, Hyatt Regency, 9801 International Dr., Orlando

Event registration and webcast information are available through the Sierra Oncology website at www.sierraoncology.com. The event will be webcast live, and an archive of the presentation will be accessible after the event through the Sierra Oncology website.

Domestic (Toll Free- US): 1 (844) 467-7642
International (Toll): 1 (417) 385-2994
Conference ID: 3577956
Webcast: www.sierraoncology.com
Direct link: View Source

ASH 2019 Momelotinib Poster Presentation Information:
Title: Dynamic and Time-To-Event Analyses Demonstrate Marked Reduction in Transfusion Requirements for Janus Kinase Inhibitor–Naïve Myelofibrosis Patients Treated with Momelotinib Compared Head to Head with Ruxolitinib
Session Name: 634. Myeloproliferative Syndromes: Clinical: Poster I
Date: Saturday, December 7th, 2019
Presentation Time: 5:30 pm – 7:30 pm ET
Location: Orange County Convention Center, Hall B

The poster will be available on Saturday, December 7th, 2019 on the company’s website at www.sierraoncology.com

On December 7, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new data on two investigational CD20-CD3 T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, in people with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) (Press release, Hoffmann-La Roche, DEC 7, 2019, View Source [SID1234552029]). Results from the phase I/Ib GO29781 study of mosunetuzumab, including data from people previously treated with chimeric antigen receptor (CAR) T-cell therapy, will be presented at the 61st American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting during the Plenary Scientific Session. The Plenary Scientific Session highlights the top six abstracts submitted to the meeting, as determined by the ASH (Free ASH Whitepaper) Program Committee. Additionally, results from the phase I/Ib NP30179 study evaluating CD20-TCB as a combination therapy with Gazyva/Gazyvaro (obinutuzumab) for people with R/R NHL, will be presented.

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"Despite recent treatment advancements, slow-growing and aggressive non-Hodgkin lymphomas present increasingly difficult management challenges with each subsequent relapse," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "We’re encouraged by these early results, which suggest that our novel bispecific cancer immunotherapies may help people with relapsed or treatment-refractory disease who need more options."

The GO29781 study evaluated mosunetuzumab in patients with R/R NHL, including patients who have relapsed following, or are resistant to, CAR T-cell therapy – a patient population with limited treatment options. Results from this dose-escalation study showed encouraging efficacy with an objective response rate (ORR) of 62.7% (n=42/67) in slow-growing NHL and 37.1% (n=46/124) in aggressive NHL. Additionally, data demonstrated a complete response (CR) rate of 43.3% (n=29/67) in slow-growing NHL and 19.4% (n=24/124) in aggressive NHL. CRs showed durability, with 82.8% (n=24/29) of patients with slow-growing NHL remaining in remission up to 26 months off initial treatment and 70.8% (n=17/24) of patients with aggressive NHL remaining in remission up to 16 months off initial treatment. Of the participants who received prior CAR T-cell therapy, the ORR was 38.9% (n=7/18), and 22.2% (n=4/18) achieved a CR. Adverse reactions included cytokine release syndrome (CRS) in 28.9% of patients with 20.0% at Grade 1 and 1.1% at Grade 3. Grade 3 neurological adverse events occurred in 3.7% of patients.

Results from the phase I/Ib dose-escalation NP30179 study, evaluating CD20-TCB at doses ranging from 0.6 mg to 16 mg plus Gazyva/Gazyvaro in people with R/R B-cell NHL, showed an ORR of 54% (n=15/28) and a CR rate of 46% (n=13/28). This included an ORR and CR of 66.7% (n=4/6) in people with follicular lymphoma and an ORR of 50.0% (n=11/22) and a CR of 40.9% (n=9/22) in aggressive NHL. The most frequently observed adverse event across all treatment doses was CRS, occurring in 67.9% of patients (n=19/28), with the majority of events being low grade (Grade 1-2).

Both mosunetuzumab and CD20-TCB continue to be evaluated in a robust clinical development programme, investigating the treatments as monotherapies and in combination with other therapies, in people with slow-growing and aggressive forms of NHL.

About Roche’s investigational bispecifics in haematology
Roche is currently developing two T-cell engaging bispecific antibodies, mosunetuzumab and CD20-TCB, designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells. Mosunetuzumab and CD20-TCB differ in their structures, and both are being developed by Roche as part of our ongoing strategy to explore multiple bispecific formats, to identify those that maximise potential clinical benefits for patients. Mosunetuzumab has a structure similar to that of a natural human antibody in that it has two ‘Fab’ regions, but is different from naturally-occurring antibodies in that one ‘Fab’ region targets CD20 and the other ‘Fab’ region targets CD3. CD20-TCB is based on a novel structural format which we call ‘2:1’, which refers to the structure of the antibody. It is engineered to have two ‘Fab’ regions which bind to CD20, and one ‘Fab’ region which binds to CD3. The clinical development programmes for mosunetuzumab and CD20-TCB include ongoing investigations of these molecules as monotherapies and in combination with other medicines, for the treatment of people with CD20-positive B-cell non-Hodgkin lymphomas, including diffuse large B-cell lymphoma and follicular lymphoma.

About the GO29781 study
The GO29781 study [NCT02500407] is a phase I/Ib, multicentre, open-label, dose-escalation study evaluating the safety and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin lymphoma. Outcome measures include best objective response rate by revised International Working Group criteria, maximum tolerated dose, and tolerability.

About the NP30179 study
The NP30179 study [NCT03075696] is a phase I/Ib, multicentre, open-label, dose-escalation study, evaluating the efficacy, safety, tolerability and pharmacokinetics of CD20-TCB. In this study, CD20-TCB is assessed as a single agent and in combination with Gazyva/Gazyvaro (obinutuzumab), following pre-treatment with a one-time, fixed dose of Gazyva/Gazyvaro, in people with relapsed or refractory B-cell non-Hodgkin lymphoma. Outcome measures include overall response rate, complete response rate per Lugano 2014 criteria, maximum tolerated dose, and tolerability.

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes idasanutlin, a small molecule which inhibits the interaction of MDM2 with p53; T-cell engaging bispecific antibodies targeting both CD20 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On December 7, 2019 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an oncology-focused pharmaceutical company, reported that two presentations highlighting new and updated data relating to XPOVIO (selinexor), the Company’s first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, will be given at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2019 Annual Meeting taking place December 7-10, 2019 in Orlando (Press release, Karyopharm, DEC 7, 2019, View Source [SID1234552028]). The first study, which will be featured in an oral presentation, describes updated data from the Phase 1b/2 STOMP study evaluating the all oral regimen of selinexor in combination with Pomalyst (pomalidomide) and low-dose dexamethasone (dex) (SPd) in patients with relapsed or refractory multiple myeloma. The second abstract, which will be featured in a poster presentation, describes new data on the use of selinexor and dexamethasone, either alone or in combination with standard approved therapies, in patients with multiple myeloma whose disease has progressed following experimental chimeric antigen receptor T-cell (CAR-T) therapy.

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"We continue to be pleased with the efficacy and safety observed in the all oral selinexor plus Pomalyst arm of the Phase 1b/2 STOMP study, where patients with Pomalyst-naïve and Revlimid (lenalidomide)-relapsed or -refractory myeloma achieved a 56% overall response rate (ORR) and a 12-month progression free survival (PFS)," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "Another key study this year is the presentation of new data from patients treated with selinexor-based regimens after their myeloma had progressed following experimental CAR-T therapy. Although these data are early, six of seven patients whose disease relapsed after CAR-T achieved a response when treated with selinexor and dexamethasone alone or in combination with either Velcade (bortezomib) or Kyprolis (carfilzomib). There is currently very limited data regarding treatment options for patients whose disease has progressed following experimental CAR-T therapy, and we believe these encouraging results further reinforce the therapeutic activity of selinexor in patients with relapsed or refractory disease."

Updated Data from Phase 1b/2 STOMP Study Evaluating Selinexor in Combination with Pomalyst and Low-dose Dexamethasone (SPd)

In this arm of the Phase 1b/2 STOMP study, oral selinexor is being evaluated in combination with Pomalyst (3 or 4mg orally, once daily) and low dose dexamethasone (orally, 40mg once weekly or 20mg twice weekly) in patients with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or patients with myeloma refractory to both a PI and an IMiD. The following table is a summary of the efficacy results:

Best Responses1 in Evaluable SPd Patients as of 1-Oct-20192
Prior Therapy Status N3 ORR VGPR4 PR Median PFS
Pomalyst-naïve and Revlimid refractory or relapsed 32 18 (56%) 6 (19%) 12 (38%) 12.2 months
Pomalyst Treated and Revlimid refractory 14 5 (36%) 1 (7%) 4 (29%) 5.6 months
Key: ORR=Overall Response Rate (VGPR+PR); VGPR=Very Good Partial Response; PR=Partial Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data
3 Five patients not evaluable for response: one death unrelated to myeloma, one non-compliance with study procedures, one withdrawal of consent before disease follow up, one death related to progressive disease (PD), one PD before C2D1
4 One unconfirmed VGPR

Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (AEs) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common non-hematologic treatment-related AEs were nausea (52%), fatigue (52%) and weight loss (39%). As expected, the most common treatment-related Grade 3 and 4 AEs were neutropenia (58%), thrombocytopenia (27%) and anemia (27%).

Based on these Phase 2 results, a Phase 3 study investigating the SPd combination is planned.

In parallel with the ongoing Phase 1b/2 STOMP study, Karyopharm is conducting the pivotal, randomized Phase 3 BOSTON study evaluating once-weekly selinexor in combination with the PI Velcade and dexamethasone (SVd) for the treatment of patients with multiple myeloma who have had one to three prior lines of therapy. Enrollment in the BOSTON study is complete and top-line data are expected in early 2020 contingent upon the occurrence of PFS events, the primary endpoint of the study. Data from the BOSTON study, if positive, are expected to be used to support regulatory submissions to the U.S. Food and Drug Administration and the European Medicines Agency requesting the use of selinexor in combination with Velcade and dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

New Data from Study Evaluating Selinexor in Patients with Multiple Myeloma Following CAR-T Therapy

In this study, seven patients were identified from selinexor myeloma trials who had received an active dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) as treatment for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. One patient was treated with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice weekly), one patient was treated with the regimen currently being investigated in the ongoing Phase 3 BOSTON study, a combination of selinexor (100 mg once-weekly), Velcade (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly), and five patients were treated with a combination of selinexor (100 mg once-weekly), Kyprolis (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once weekly or 20 mg twice weekly). Patients had a median of ten prior therapeutic regimens (range: 5-15), all had high-risk cytogenetics, and six of the seven had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days).

The following table is a summary of the efficacy results:

Best Responses1 in Evaluable Patients2
N ORR sCR VGPR PR
All patients 7 6 (86%) 1 (14%) 3 (43%) 2 (29%)
Key: ORR=Overall Response Rate (CR+VGPR+PR); sCR=Stringent Complete Response
1 Responses were adjudicated according to the International Myeloma Working Group criteria
2 Based on interim unaudited data

Of the six patients who responded (≥PR), the duration of response ranged from 1.4 months to 7.4 months, with two patients still on therapy and responding. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia.

These preliminary data suggest that selinexor-dexamethasone alone or in combination with Velcade or Kyprolis may offer a therapeutic option for patients who have exhausted other available treatments, have rapidly progressing disease, and who have progressed after CAR-T therapy.

Details for these two ASH (Free ASH Whitepaper) 2019 presentations are as follows:

Oral Presentation

Title: Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma
Presenter: Christine Chen, Princess Margaret Cancer Centre
Abstract #: 141
Session: 653. Myeloma: Therapy, excluding Transplantation: New Approaches in the Treatment of Relapsed/Refractory Plasma Cell Discrasias
Date and Time: Saturday, December 7, 2019; 9:30-11:00 AM ET
Location: Orange County Convention Center, Hall E1
Poster Presentation – Company-Sponsored Studies

Title: Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy
Presenter: Ajai Chari, Icahn School of Medicine at Mount Sinai
Abstract #: 1854
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Date and Time: Saturday, December 7, 2019; 5:30-7:30 PM ET
Location: Orange County Convention Center, Hall B

PDF copies of these presentations will be available here following conclusion of the presentations at the meeting.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. In addition to receiving accelerated FDA approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor. Selinexor is also being studied in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In 2018, Karyopharm reported positive top-line results from the Phase 2b SADAL study evaluating selinexor in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue. Selinexor has received Fast Track designation from the FDA for the patient population evaluated in the SADAL study. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL), in recurrent gliomas (KING) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

IMPORTANT SAFETY INFORMATION

Thrombocytopenia

XPOVIO can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with XPOVIO. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in <1% of patients.

Monitor platelet counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia

XPOVIO can cause neutropenia, potentially increasing the risk of infection. Neutropenia was reported as an adverse reaction in 34% of patients, and severe (Grade 3-4) neutropenia occurred in 21% of patients treated with XPOVIO. The median time to onset of the first event was 25 days. Febrile neutropenia was reported in 3% of patients.

Obtain neutrophil counts at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures including antimicrobials for signs of infection and use of growth factors (e.g., G-CSF). Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity

Gastrointestinal toxicities occurred in patients treated with XPOVIO.

Nausea/Vomiting

Nausea was reported as an adverse reaction in 72% of patients, and Grade 3 nausea occurred in 9% of patients treated with XPOVIO. The median time to onset of the first nausea event was 3 days.

Vomiting was reported in 41% of patients, and Grade 3 vomiting occurred in 4% of patients treated with XPOVIO. The median time to onset of the first vomiting event was 5 days.

Provide prophylactic 5-HT3 antagonists and/or other anti-nausea agents, prior to and during treatment with XPOVIO. Manage nausea/vomiting by dose interruption, reduction, and/or discontinuation. Administer intravenous fluids and replace electrolytes to prevent dehydration in patients at risk. Use additional anti-nausea medications as clinically indicated.

Diarrhea

Diarrhea was reported as an adverse reaction in 44% of patients, and Grade 3 diarrhea occurred in 6% of patients treated with XPOVIO. The median time to onset of diarrhea was 15 days.

Manage diarrhea by dose modifications and/or standard anti-diarrheal agents; administer intravenous fluids to prevent dehydration in patients at risk.

Anorexia/Weight Loss

Anorexia was reported as an adverse reaction in 53% of patients, and Grade 3 anorexia occurred in 5% of patients treated with XPOVIO. The median time to onset of anorexia was 8 days.

Weight loss was reported as an adverse reaction in 47% of patients, and Grade 3 weight loss occurred in 1% of patients treated with XPOVIO. The median time to onset of weight loss was 15 days.

Monitor patient weight at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Manage anorexia and weight loss with dose modifications, appetite stimulants, and nutritional support.

Hyponatremia

XPOVIO can cause hyponatremia; 39% of patients treated with XPOVIO experienced hyponatremia, 22% of patients experienced Grade 3 or 4 hyponatremia. The median time to onset of the first event was 8 days.

Monitor sodium level at baseline, during treatment, and as clinically indicated. Monitor more frequently during the first two months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction.

Infections

In patients receiving XPOVIO, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.

Neurological Toxicity

Neurological toxicities occurred in patients treated with XPOVIO.

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with XPOVIO. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, XPOVIO can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the XPOVIO dose, and 65.3% had the dose of XPOVIO interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received XPOVIO included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.